title: Polymorphisms in CYP3A5, CYP3A4, and ABCB1 are not associated with cyclosporine pharmacokinetics nor with cyclosporine clinical end points after renal transplantation.
abstract: BACKGROUND
  The association of CYP3A5, CYP3A4, and ABCB1 single nucleotide polymorphisms (SNPs) with cyclosporine (CsA) pharmacokinetics is controversial. The authors studied the influence of these SNPs on CsA pharmacokinetics as well as on the incidence of biopsy-proven acute rejection (BPAR) and renal function after kidney transplantation.
  
  
  METHODS
  One hundred seventy-one patients participating in an international, randomized controlled trial were genotyped for CYP3A5*3, CYP3A4*1B and the ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T SNPs. The patients were treated with CsA, mycophenolate mofetil, and glucocorticoids. CsA was dosed to reach predose concentrations (C0) or two hours postdose concentrations (C2). Pharmacokinetic parameters were measured on Days 3 and 10 and Months 1, 3, 6, and 12 after transplantation. Renal function was assessed by measuring serum creatinine and calculating the creatinine clearance. The incidence of BPAR and delayed-graft function was recorded.
  
  
  RESULTS
  CYP3A5, CYP3A4, and ABCB1 genotype were not associated with dose-adjusted CsA C0 or C2. The incidence of BPAR in this cohort was 16% and was comparable between the different ABCB1 genotype groups. No significant difference in the incidence of BPAR was found between CYP3A5 expressers (10%) and nonexpressers (18%) (P = 0.24) nor was there a difference in the incidence of BPAR between CYP3A4*1 homozygotes (5%) versus CYP3A4*1B carriers (18%) (P = 0.13). There were no differences with regard to creatinine clearance between the different CYP3A and ABCB1 genotype groups.
  
  
  CONCLUSIONS
  According to the results, determination of CYP3A and ABCB1 SNPs pretransplantation is not helpful in determining the CsA starting dose and does not aid in predicting the risk of BPAR or worse renal function in an individual patient.
authors.affiliation: Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, Rotterdam, The Netherlands. r.bouamar@erasmusmc.nl
authors.forename: Rachida
authors.initials: R
authors.lastname: Bouamar
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Hesselink
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Iain A M
authors.initials: IA
authors.lastname: Macphee
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D016572:Cyclosporine / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D051799:Delayed Graft Function / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use; D006084:Graft Rejection / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D038622:Internationality; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009173:Mycophenolic Acid